This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in identifying compounds that may be antagonists and/or antagonists that are potentially useful in therapy, and to production of such polypeptides and polynucleotides.
The drug discovery process is currently undergoing a fundamental revolution as it embraces xe2x80x98functional genomics,xe2x80x99 that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on xe2x80x98positional cloningxe2x80x99. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery.
There are currently five known human aspartic proteases (or proteinases), namely, pepsin, gastricsin, cathepsin D, cathepsin E and renin, and these have widely varying functions. Pepsin and gastricsin are involved in nutritive processes in the stomach; cathepsin D is involved in protein turnover in many cell types; and renin has the highly specific function of angiotensin production from its precursor form, angiotensinogen. The precise role of cathepsin E remains to be confirmed, although its location in some epithelial cell types has indicated a role in antigen processing. It may also be involved in certain inflammatory conditions, such as Helicobacter pylori infection in the stomach. This indicates that the Aspartic Proteinase family has an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of Aspartic Proteinase family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, Alzheimer""s Disease, cancer, and prohormone processing.
The present invention relates to mASP-2, in particular mASP-2 polypeptides and mASP-2 polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for identifying antagonists and antagonists/inhibitors of the mouse mASP-2 gene. This invention further relates to the generation of in vitro and in vivo comparison data relating to the polynucleotides and polypeptides in order to predict oral absorption and pharmacokinetics in man of compounds that either agonize or antagonize the biological activity of such polynucleotides or polypeptides. Such a comparison of data will enable the selection of drugs with optimal pharmacokinetics in man, i.e., good oral bioavailability, blood-brain barrier penetration, plasma half-life, and minimum drug interaction.
The present invention further relates to methods for creating transgenic animals, which overexpress or underexpress or have regulatable expression of a mASP-2 gene and xe2x80x9cknock-outxe2x80x9d animals, preferably mice, in which an animal no longer expresses a mASP-2 gene. Furthermore, this invention relates to transgenic and knock-out animals obtained by using these methods. Such animal models are expected to provide valuable insight into the potential pharmacological and toxicological effects in humans of compounds that are discovered by the aforementioned screening methods as well as other methods. An understanding of how a mouse mASP-2 gene functions in these animal models is expected to provide an insight into treating and preventing human diseases including, but not limited to: Alzheimer""s disease, cancer and prohormone processing, hereinafter referred to as xe2x80x9cthe Diseasesxe2x80x9d, amongst others.